Doxorubicin is a known chemotherapeutic agent administered mainly by intravenous injection to cancer suffering patients. Because of its complex structure, doxorubicin exhibits limited solubility in physiological fluids. In addition, doxorubicin is not fully transmitted across cell membranes and binds with plasma protein, as well as undergoes other non-specific interactions in the bloodstream before doxorubicin can reach the target cancer. This has caused doxorubicin to be utilized at high dosages so that a therapeutic does reaches the target cancer. Since doxorubicin has very strong side effects the use of high dosages can be very disadvantageous.
In order to avoid some of these problems doxorubicin and other chemotherapeutic agents have been formulated utilizing polyoxyethylene polypropylene block copolymer mixtures which allow the chemotherapeutic agent, particularly doxorubicin and its pharmaceutically acceptable salts, to be solubilized in aqueous medium and physiological fluids, and be effectively transported to its targets. The use of these copolymer mixtures to solubilize chemotherapeutic agents, particularly doxorubicin and its pharmaceutically acceptable salts, is disclosed in U.S. Pat. No. 5,698,529; U.S. Pat. No. 5,817,321; U.S. Pat. No. 6,060,518; U.S. Pat. No. 6,227,410 and U.S. Pat. No. 6,387,406.
The use of these block copolymers to prepare injectable solutions has been fraught with difficulty. In particularly the hydrophilic block copolymer and the hydrophobic block copolymer are waxy and adhesive solids. The handling of such materials in preparing injectable solutions is difficult, and requires special manufacturing procedures and quality control. The dissolution of such material is often slow and difficult to control. Therefore the use of waxy solid materials for precise dosing of strong biologically active compounds makes their use difficult in preparing injectable solutions for clinical practice. In addition, such solutions have to be prepared about or near the time of their use. In this regard, chemical stability of the components after reconstitution in aqueous media is often limited, and pre-made solutions are often not acceptable forms for medical use by injection.
It is therefore suggested to modify the mentioned composition with biologically non-active components to obtain an instantly soluble composition. Such modifications of injectable solutions can be difficult. Several components which could potentially be used in the formulation mixture, to accelerate the dissolution of the given composition, are not suitable for injectable solutions. The requirement that a product mixture be administered by injection limits the admixtures to only those materials which are biologically inert, stable and compatible.
Furthermore, it has been found that these compositions containing doxorubicin have limited stability and can deteriorate on standing. Therefore, once these compositions are produced they should be used for delivering doxorubicin to the patient immediately so as to avoid any decomposition. The products cannot be prepared in bulk and then later dispensed into unit injectable dosage form for administration to the patients. Once these compositions have been formulated in a liquid aqueous medium and dried, these compositions cannot be reproducibly reconstituted by the addition of water.
Therefore, it has long been desired to prepare doxorubicin as a stable liquid composition where it can be stored for long periods of time, dried and shipped and thereafter reproducibly reconstituted in a soluble form which can be administered to patients in the same therapeutic reactive form in which the composition was initially formulated.